Introduction: High grade ovarian cancer (HGOC) is an agressive disease with
unfavourable clinical course. Most of the tumors have no precursor lesion and
develop rapidly. They reveal genetic alterations such as BRCA1- and p53-
mutations. These tumors are primarily highly responsive to platinum-based
therapy but after several courses of treatment acquire resistence. There is a
strong need of new prognostic and predictive factors, which can help better
address this clinical challenge. Recent studies brought evidence that patients
with BRCA1 mutation have a favourable prognosis. Among the sporadic HGOC the
aberrant methylation of the BRCA1 promotor region represent an alternative
mechanism of BRCA1 gene silencing. We aimed to examine the clinical importance
of BRCA1 gene dysfunction in HGOC patients. Furthermore we analysed the EpCAM
expression in tumour tissues from matched primary and recurrent HGOC patients.
Methods: Blood samples and fresh frozen tissue from HGOC patients, treated at
the Charité Klinik Berlin between 2000 and 2011 were collected from TOC (Tumor
Ovarian Cancer) Network. Direct sequencing of exon 11 was performed as method
for BRCA1 mutation detection for 263 HGOC patients. BRCA1 gene promothor hyper
methylation rate was assessed using real time PCR among 257 HGSOC patients.
The EpCAM overexpression in 19 matched tumour tissue samples was measured with
immunohistochemistry. Results: Mutations in BRCA1 exon 11 were found in 18 of
263 patients (6.8 %). Further 10/263 (3.8 %) cases showed variants of
uncertain importance (VUS). All exon 11 BRCA1-positive tumours were high grade
serous (p=0.05). The BRCA1 exon 11 mutational status was not found to be an
independent predicitive factor for optimal cytoreduction, platinum response or
survival. A BRCA1 promotor hypermethylation was found in 38 of 257 samples
(14.8 %). The rate of hypermethylation was significantly higher in younger
patients (20.8 % < 58 J. vs 8.7 % >58 J., p=0.008). The BRCA1 hypermethylation
did not influence the PFS or OS rates between the groups. The EpCAM expression
analysis revealed an EpCAM overexpression in 17 (89 %) of the primary and 16
(84 %) of the recurrent tumours (p=1.0). Conclusion: A BRCA1-mutation in exon
11 was found predominantly among the HGOC. A BRCA1 promotor hypermethylation
was detected more frequently among younger patients. Although the BRCA1
mutational status and BRCA1 methylation did not influence the clinical oucome
in this population, the BRCA 1 gene dysfuncion might be of interest as factor
for tailoring the oncologic treatment among HGOC. In the setting of recurrent
HGOC the EpCAM overexpression might be also a possible treatment target.